mCRC: Stratifying Patients to Appropriate Therapy

Howard S. Hochster, MD, FACP: Based on the data that have come out of the CALGB/SWOG 80405 trial—and that was for all RAS wild-type patients—and also the FIRE-3 trial in Europe, we’ve come to this realization that patients who have right-sided colon cancer actually have a much worse prognosis than those with left-sided colon cancer. There’s maybe, in terms of median survival, a year’s difference just on the basis of sidedness. So I’d like to think of that as a poor man’s molecular biology test that we don’t really understand all the molecular implications of. But, even with therapy or without it, those patients have a worse biology.

In addition, besides the fact that we know that the EGFR antibodies don’t work for people who have RAS mutations, it seems like they also don’t work and may actually be somewhat harmful in patients with right-sided colon cancer. So I think that today, everybody recognizes that you shouldn’t give anti-EGFR antibodies to patients with right-sided colon cancer, in addition to patients who have RAS mutations, especially in the first line. The data in subsequent lines are somewhat supportive too, but those are retrospective molecular subset data, so they’re not quite as clear.

And so that limits the use of anti-EGFR antibodies to RAS wild-type patients who have left-sided tumors, and those are the patients who will benefit the most from those antibodies. Again, in addition to the right-sided patients, we need to bring out the patients who have BRAF mutations. Again, for the patients who have right-sided colon cancer, we need to be especially aware of the fact that they have BRAF mutations or microsatellite instability [MSI]. So all patients need to be tested today and then directed to appropriate trials.

For the MSI-high patients, there’s an NRG SWOG trial, the COMMIT trial, looking at antibodies alone versus antibodies in combination with chemotherapy for MSI-high patients in the first line. This is a really important study. The question of the combination hasn’t been addressed by anybody else. And also we know that tumors that have mismatch repair deficiencies are more sensitive to platinums and other DNA-damaging agents. So the chemotherapy works better for these patients, as well, so we really do need to ask the question: Should you give the anti-PD-1 drug alone or together with chemotherapy, or should you give chemotherapy first and anti–PD-1 second? And this NCI [National Cancer Institute]–sponsored trial will answer that question.

Transcript Edited for Clarity

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Transcript:

Howard S. Hochster, MD, FACP: Based on the data that have come out of the CALGB/SWOG 80405 trial—and that was for all RAS wild-type patients—and also the FIRE-3 trial in Europe, we’ve come to this realization that patients who have right-sided colon cancer actually have a much worse prognosis than those with left-sided colon cancer. There’s maybe, in terms of median survival, a year’s difference just on the basis of sidedness. So I’d like to think of that as a poor man’s molecular biology test that we don’t really understand all the molecular implications of. But, even with therapy or without it, those patients have a worse biology.

In addition, besides the fact that we know that the EGFR antibodies don’t work for people who have RAS mutations, it seems like they also don’t work and may actually be somewhat harmful in patients with right-sided colon cancer. So I think that today, everybody recognizes that you shouldn’t give anti-EGFR antibodies to patients with right-sided colon cancer, in addition to patients who have RAS mutations, especially in the first line. The data in subsequent lines are somewhat supportive too, but those are retrospective molecular subset data, so they’re not quite as clear.

And so that limits the use of anti-EGFR antibodies to RAS wild-type patients who have left-sided tumors, and those are the patients who will benefit the most from those antibodies. Again, in addition to the right-sided patients, we need to bring out the patients who have BRAF mutations. Again, for the patients who have right-sided colon cancer, we need to be especially aware of the fact that they have BRAF mutations or microsatellite instability [MSI]. So all patients need to be tested today and then directed to appropriate trials.

For the MSI-high patients, there’s an NRG SWOG trial, the COMMIT trial, looking at antibodies alone versus antibodies in combination with chemotherapy for MSI-high patients in the first line. This is a really important study. The question of the combination hasn’t been addressed by anybody else. And also we know that tumors that have mismatch repair deficiencies are more sensitive to platinums and other DNA-damaging agents. So the chemotherapy works better for these patients, as well, so we really do need to ask the question: Should you give the anti-PD-1 drug alone or together with chemotherapy, or should you give chemotherapy first and anti–PD-1 second? And this NCI [National Cancer Institute]–sponsored trial will answer that question.